Breast AdenocarcinomaPhase 3NCT00005970
Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer
A Phase 3 study testing Aromatase Inhibition Therapy, Cyclophosphamide and Doxorubicin Hydrochloride in people with Breast Adenocarcinoma and HER2 Positive Breast Carcinoma, run by National Cancer Institute (NCI) at 157 sites in 4 countries.
Trial summary
This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer that is human epidermal growth factor receptor 2 (HER2)-positive and has spread to the lymph nodes… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Adenocarcinoma, HER2 Positive Breast Carcinoma, Stage IA Breast Cancer AJCC v7
- What is being tested?
- Aromatase Inhibition Therapy, Cyclophosphamide and Doxorubicin Hydrochloride
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3,436 participants
- Where
- 157 sitesin 4 countries
- Study dates
- 19 May 2000to 27 Jan 2010
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Required tumor parameters for node positive disease: NOTE: This study will continue to use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification and staging
- Operable, histologically confirmed adenocarcinoma of the female breast and positive lymph nodes
- Node positivity may be determined by either an axillary node dissection or a positive sentinel node finding by hematoxylin and eosin (H\&E)
- NOTE: Positive nodes refers to H\&E visible nodal metastases; immunohistochemistry (IHC) positive only cells in lymph nodes will not be considered positive nodes
- One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are eligible
- cN2 disease is not eligible
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- pN2 disease is eligible
- One positive lymph node by sentinel node biopsy or at least 6 axillary nodes must be examined on axillary node dissection with at least one positive lymph node
- Metaplastic carcinoma is eligible
- ER/PgR determination
- HER-2 positive (pre-entry requirement for registration)
- FISH must show gene amplification OR
- IHC assay must show a strong positive (3+) staining score
- NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification
- Required tumor parameters for high-risk node-negative disease; NOTE: This study will continue to use the AJCC 5th edition for TNM classification and staging
- Operable, histologically confirmed adenocarcinoma of the female breast and negative lymph nodes
- Node status may be determined by either axillary node dissection or sentinel node biopsy with H\&E staining; to be considered node negative, either of the following must be true: 1) negative sentinel node biopsy or 2) no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection
- NOTE: IHC positive only cells in lymph nodes will not be considered positive nodes
- Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if ER-negative and PR-negative disease
- ER/PgR determination
- HER-2 positive (pre-entry requirement for registration)
- FISH must show gene amplification OR
- IHC assay must show a strong positive (3+) staining score
- NOTE: DCIS components should not be counted in the determination of degree of IHC staining or FISH amplification
- =< 84 days from mastectomy or =< 84 days from axillary dissection or sentinel node detection if the patient's most extensive breast surgery was a breast sparing procedure; (This timing is per a decision by the Breast Intergroup)
- Surgical resection margins. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy with axillary node dissection
- Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or DCIS) at the surgical resection margins noted in the final surgery or pathology reports; patients with close margins are eligible
- Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and DCIS
- Axillary dissection or sentinel node dissection: There will be no gross residual adenopathy
- TAM therapy
- May have received up to four weeks of TAM therapy, or any other hormonal agent, for this malignancy
- May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before registration on this study
- May never have received TAM, raloxifene, or any other hormonal agent
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Platelets (PLT) >= 100,000/mm^3
- Total bilirubin =< 1.5 x upper normal limit (UNL)
- Aspartate aminotransferase (AST) =< 2.0 x UNL
- Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF is > 75%, the investigator should consider performing a second review of the multigated acquisition (MUGA)/echocardiogram or performing a repeat MUGA/echocardiogram prior to registration; such re-reviews or repeat MUGA/echocardiogram are not permitted after registration
- Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc., prior to registration and while on study
- Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to registration and while on study
- Non-breast malignancies that have not recurred within the last 5 years and are deemed to be at low risk for recurrence
- EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed =< 5 years prior to registration:
- Squamous or basal cell carcinoma of the skin that has been effectively treated
- Carcinoma in situ of the cervix that has been treated by surgery only
- Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by surgery and/or tamoxifen only
- Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary dissection) must have plans to receive radiation therapy to the breast +/- regional lymphatics following completion of the chemotherapy; for patients treated with mastectomy, the use of radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy; the use of radiation therapy is at the discretion of the investigator for 0-3 positive lymph nodes but, if used, must be started after the completion of chemotherapy
- Prior to registration, the physician must designate if it is planned for the patient to receive radiation therapy (for adjuvant radiation therapy post-mastectomy or, less commonly, post-conservative therapy but not primary breast radiation as part of breast conserving treatment)
- Willing and able to sign an informed consent
- Gene amplified by FISH or strong positivity (3+) by HercepTest on central review; Note: The patient registers based on community HER-2 testing using FISH or IHC, AC chemotherapy is initiated; the tumor block or slides must be received =< 2 weeks from time of registration to the North Central Cancer Treatment Group (NCCTG) Operations Office for central HER-2 testing
Who cannot join
- Any of the following:
- Pregnant women
- Nursing women
- Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, intrauterine device [IUD], surgical sterilization, or abstinence, etc.); hormonal birth control methods are not permitted
- Locally advanced tumors (classification T4) at diagnosis including tumors fixed to chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)
- Prior history of breast cancer, except LCIS
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- Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of the contralateral breast treated with mastectomy are eligible)
- Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer
- Active, unresolved infection
- Active cardiac disease
- Any prior myocardial infarction
- History of documented congestive heart failure (CHF)
- Current use of digitalis or beta-blockers for CHF
- Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant
- Current use of medications for treatment of arrhythmias or angina pectoris
- Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)
- Clinically significant pericardial effusion
- Prior anthracycline or taxane therapy for any malignancy
- Sensitivity to benzyl alcohol
- Neurology/Neuropathy-Sensory >= grade 2 per the National Cancer Institute's (NCI's) Common Toxicity Criteria Version 2.0; EXCEPTION: Any chronic neurologic disorder will be looked at on a case-by-case basis by the study chair
Trial locations and contacts
157 sites in 4 countries.
157 sites in 4 countries
United States154 sites
The Don and Sybil Harrington Cancer Center
Amarillo, Texas, 79106
Michigan Cancer Research Consortium NCORP
Ann Arbor, Michigan, 48106
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Mission Hospital Inc-Memorial Campus
Asheville, North Carolina, 28801
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Atlanta Regional CCOP
Atlanta, Georgia, 30342
University of Colorado Hospital
Aurora, Colorado, 80045
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Southwestern Vermont Medical Center
Bennington, Vermont, 05201
Walter Reed National Military Medical Center
Bethesda, Maryland, 20889-5600
Montana Cancer Consortium NCORP
Billings, Montana, 59102
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Sanford Bismarck Medical Center
Bismarck, North Dakota, 58501
Tufts Medical Center
Boston, Massachusetts, 02111
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Boston Medical Center
Boston, Massachusetts, 02118
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Roswell Park Cancer Institute
Buffalo, New York, 14263
University of Vermont and State Agricultural College
Burlington, Vermont, 05405
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Roper Hospital
Charleston, South Carolina, 29401
Medical University of South Carolina
Charleston, South Carolina, 29425
Sentara Martha Jefferson Hospital
Charlottesville, Virginia, 22901
Northwestern University
Chicago, Illinois, 60611
Rush University Medical Center
Chicago, Illinois, 60612
University of Illinois
Chicago, Illinois, 60612
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
University of Cincinnati/Barrett Cancer Center
Cincinnati, Ohio, 45219
Case Western Reserve University
Cleveland, Ohio, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Community Cancer Institute
Clovis, California, 93611
University of Missouri - Ellis Fischel
Columbia, Missouri, 65212
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
Geisinger Medical Center
Danville, Pennsylvania, 17822
Heartland Cancer Research NCORP
Decatur, Illinois, 62526
Iowa-Wide Oncology Research Coalition NCORP
Des Moines, Iowa, 50309
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
Henry Ford Hospital
Detroit, Michigan, 48202
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Essentia Health Cancer Center
Duluth, Minnesota, 55805
Duke University Medical Center
Durham, North Carolina, 27710
Englewood Hospital and Medical Center
Englewood, New Jersey, 07631
University of Oregon
Eugene, Oregon, 97403-1217
Sanford Broadway Medical Center
Fargo, North Dakota, 58122
Brooke Army Medical Center
Fort Sam Houston, Texas, 78234
Washington Hospital
Fremont, California, 94538
Northeast Georgia Medical Center-Gainesville
Gainesville, Georgia, 30501
University of Texas Medical Branch
Galveston, Texas, 77555-0565
Glendale Memorial Hospital and Health Center
Glendale, California, 91204
Altru Cancer Center
Grand Forks, North Dakota, 58201
Cancer Research Consortium of West Michigan NCORP
Grand Rapids, Michigan, 49503
Cone Health Cancer Center
Greensboro, North Carolina, 27403
Hackensack University Medical Center
Hackensack, New Jersey, 07601
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, 17033-0850
University of Hawaii Cancer Center
Honolulu, Hawaii, 96813
New Hampshire Oncology Hematology PA-Hooksett
Hooksett, New Hampshire, 03106
Indiana University/Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
University of Mississippi Medical Center
Jackson, Mississippi, 39216
Mayo Clinic in Florida
Jacksonville, Florida, 32224-9980
Kalamazoo Center for Medical Studies
Kalamazoo, Michigan, 49008
CHI Health Good Samaritan
Kearney, Nebraska, 68847
Wellmont Holston Valley Hospital and Medical Center
Kingsport, Tennessee, 37660
Thompson Cancer Survival Center
Knoxville, Tennessee, 37916
University of Tennessee - Knoxville
Knoxville, Tennessee, 37920
University Medical Center of Southern Nevada
Las Vegas, Nevada, 89102
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, 03756
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
North Shore University Hospital
Manhasset, New York, 11030
Loyola University Medical Center
Maywood, Illinois, 60153
University of Tennessee Health Science Center
Memphis, Tennessee, 38163
Milford Regional Medical Center
Milford, Massachusetts, 01757
Froedtert and the Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455
Memorial Medical Center
Modesto, California, 95355
Community Hospital of Monterey Peninsula
Monterey, California, 93940
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Long Island Jewish Medical Center
New Hyde Park, New York, 11040
Tulane University Health Sciences Center
New Orleans, Louisiana, 70112
Ochsner Medical Center Jefferson
New Orleans, Louisiana, 70121
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
Mount Sinai Hospital
New York, New York, 10029
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
NYP/Weill Cornell Medical Center
New York, New York, 10065
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Missouri Valley Cancer Consortium
Omaha, Nebraska, 68106
University of Nebraska Medical Center
Omaha, Nebraska, 68198
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
AdventHealth Orlando
Orlando, Florida, 32803
Stanford Cancer Institute Palo Alto
Palo Alto, California, 94304
Memorial Hospital of Rhode Island
Pawtucket, Rhode Island, 02860
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, 19104
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111
Western Regional CCOP
Phoenix, Arizona, 85006
Via Christi Hospital-Pittsburg
Pittsburg, Kansas, 66762
West Penn Hospital
Pittsburgh, Pennsylvania, 15224
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232
Providence Portland Medical Center
Portland, Oregon, 97213
Kansas City NCI Community Oncology Research Program
Prairie Village, Kansas, 66208
Rhode Island Hospital
Providence, Rhode Island, 02903
Rapid City Regional Hospital
Rapid City, South Dakota, 57701
Mayo Clinic
Rochester, Minnesota, 55905
University of Rochester
Rochester, New York, 14642
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
Coborn Cancer Center at Saint Cloud Hospital
Saint Cloud, Minnesota, 56303
Metro Minnesota Community Oncology Research Consortium
Saint Louis Park, Minnesota, 55416
Salina Regional Health Center
Salina, Kansas, 67401
Salinas Valley Memorial
Salinas, California, 93901
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
University of Texas Health Science Center at San Antonio
San Antonio, Texas, 78229
University of California San Diego
San Diego, California, 92103
Naval Medical Center -San Diego
San Diego, California, 92134
UCSF Medical Center-Mount Zion
San Francisco, California, 94115
The Angeles Clinic and Research Institute - Santa Monica Office
Santa Monica, California, 90404
Santa Rosa Memorial Hospital
Santa Rosa, California, 95405
Memorial Health University Medical Center
Savannah, Georgia, 31404
Mayo Clinic in Arizona
Scottsdale, Arizona, 85259
Virginia Mason Medical Center
Seattle, Washington, 98101
Kaiser Permanente Washington
Seattle, Washington, 98112
Louisiana State University Health Sciences Center Shreveport
Shreveport, Louisiana, 71103
Siouxland Regional Cancer Center
Sioux City, Iowa, 51101
Sanford NCI Community Oncology Research Program of the North Central Plains
Sioux Falls, South Dakota, 57104
Northern Indiana Cancer Research Consortium
South Bend, Indiana, 46628
Ascension Providence Hospitals - Southfield
Southfield, Michigan, 48075
Cancer Research for the Ozarks NCORP
Springfield, Missouri, 65804
Washington University - Jewish
St Louis, Missouri, 63110
Washington University School of Medicine
St Louis, Missouri, 63110
Missouri Baptist Medical Center
St Louis, Missouri, 63131
Saint Louis-Cape Girardeau CCOP
St Louis, Missouri, 63141
State University of New York Upstate Medical University
Syracuse, New York, 13210
SUNY Upstate Medical Center-Community Campus
Syracuse, New York, 13215
Northwest NCI Community Oncology Research Program
Tacoma, Washington, 98405
Moffitt Cancer Center
Tampa, Florida, 33612
Montefiore Medical Center-Weiler Hospital
The Bronx, New York, 10461
Toledo Community Hospital Oncology Program CCOP
Toledo, Ohio, 43617
Cotton O'Neil Cancer Center / Stormont Vail Health
Topeka, Kansas, 66606
Saint Francis Hospital and Medical Center - Topeka
Topeka, Kansas, 66606
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
Carle Cancer Center
Urbana, Illinois, 61801
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007
Wichita NCI Community Oncology Research Program
Wichita, Kansas, 67214
Wilson Medical Center
Wilson, North Carolina, 27893
Novant Health Forsyth Medical Center
Winston-Salem, North Carolina, 27103
Southeast Clinical Oncology Research (SCOR) Consortium NCORP
Winston-Salem, North Carolina, 27104
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
Saint Vincent Hospital/Reliant Medical Group
Worcester, Massachusetts, 01608
University of Massachusetts Medical School
Worcester, Massachusetts, 01655
Lankenau Medical Center
Wynnewood, Pennsylvania, 19096
About this study
Official title: Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-Expressing or Amplified Node Positive or High-Risk Node Negative Breast Cancer
This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer that is human epidermal growth factor receptor 2 (HER2)-positive and has spread to the lymph nodes or high-risk and has not spread to the lymph nodes. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without trastuzumab in treating breast cancer.
Read the detailed description
PRIMARY OBJECTIVES:
- To compare the combination of doxorubicin hydrochloride and cyclophosphamide (AC) followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of disease free survival (DFS). (Stage I) II. To compare the combination of AC followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of the rate of cardiac events. (Stage I) III. To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of DFS. (Stage II) IV. To compare the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of DFS. (Stage II) V. To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of the rate of cardiac events. (Stage II)
SECONDARY OBJECTIVES:
- To compare the combination of AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of overall survival (OS).
II. To compare the combination AC followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.
III. To compare the sequential schedule of the combination AC, weekly paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.
TERTIARY OBJECTIVES:
- To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to human epidermal growth factor receptor (HER)-2 and HER-1 measured in the serum prior to treatment are prognostic for DFS and survival.
II. To determine the concordance of central review of HER-2 overexpression as measured by the HercepTest (DAKO) and Vysis fluorescence in situ hybridization (FISH).
III. For each treatment arm, levels of brain natriuretic peptide (BNP), troponin-T (TnT), troponin-I (cTnI), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6), CD40 ligand, and troponin levels will be compared and contrasted.
IV. To determine whether genetic markers are prognostic for cardiac adverse events associated with treatment.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I*: Patients receive doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.
ARM II*: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.
ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity.
Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal estrogen receptor (ER)- or progesterone receptor (PR)-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 15 years or until disease progression.
- Conditions
- Breast Adenocarcinoma, HER2 Positive Breast Carcinoma, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7
- Being tested
- Aromatase Inhibition Therapy, Cyclophosphamide, Doxorubicin Hydrochloride, Laboratory Biomarker Analysis, Paclitaxel
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Aromatase Inhibition TherapyDrug
Also called Aromatase Inhibition
Given orally
CyclophosphamideDrug
Also called (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida
Given IV
Also called 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin
Given IV
Laboratory Biomarker AnalysisOther
Correlative studies
PaclitaxelDrug
Also called Anzatax, Asotax, Bristaxol, Praxel
Given IV
Tamoxifen CitrateDrug
Also called Apo-Tamox, Clonoxifen, Dignotamoxi, Ebefen
Given orally
TrastuzumabBiological
Also called ABP 980, ALT02, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor) | Experimental | Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy. Receives: Drug: Aromatase Inhibition Therapy; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Drug: Tamoxifen Citrate |
| Arm II (AC, paclitaxel, trastuzumab, tamoxifen) | Experimental | Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy. Receives: Drug: Aromatase Inhibition Therapy; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Drug: Tamoxifen Citrate; Biological: Trastuzumab |
| Arm III (AC, paclitaxel, trastuzumab, tamoxifen) | Experimental | Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity.
Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy. Receives: Drug: Aromatase Inhibition Therapy; Drug: Cyclophosphamide; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Drug: Tamoxifen Citrate; Biological: Trastuzumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Duration of DFS
Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether DFS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for DFS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.
Measured: Time from registration to first adverse event, assessed up to 15 years
Secondary outcomes (1)
Overall survival
Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether OS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for OS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.
Measured: Time from registration to death due to any cause, assessed up to 15 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2003 (estimated)
- Study start19 May 2000
- Primary completion25 Apr 2005
- Study completion27 Jan 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Breast AdenocarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 3,436 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Collaborators
- Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Canadian Cancer Trials Group, SWOG Cancer Research Network
- Responsible party
- Sponsor
- Investigators
- Edith A Perez, Principal investigator, Alliance for Clinical Trials in Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00005970
- Sponsor's protocol ID
- NCI-2012-01849
- Other IDs
- NCI-2012-01849, 9343, ECOG-N9831, CAN-NCIC-MA28, SWOG-N9831, MA.28, NCCTG-N9831, CALGB-49909
- Status last verified
- Aug 2020
- First submitted
- 5 Jul 2000
- Last updated
- 14 Aug 2020
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Chumsri S, Pai T, Ma Y, Li Z, Gil A, Moreno-Aspitia A, Colon-Otero G, Pogue-Geile KL, Rasgoti P, Paik S, Perez EA, Thompson EA. Clinical Treatment Score Post-5 Years (CTS5) and Late Recurrence Risk in Hormone Receptor-Positive, HER2-Positive Breast Cancer. J Natl Compr Canc Netw. 2024 Aug 26;22(7):463-468. doi: 10.6004/jnccn.2024.7015.
PubMed 39191270Chumsri S, Li Z, Serie DJ, Norton N, Mashadi-Hossein A, Tenner K, Brauer HA, Warren S, Danaher P, Colon-Otero G, Partridge AH, Carey LA, Hilbers F, Van Dooren V, Holmes E, Di Cosimo S, Werner O, Huober JB, Dueck AC, Sotiriou C, Saura C, Moreno-Aspitia A, Knutson KL, Perez EA, Thompson EA. Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials. NPJ Breast Cancer. 2022 May 24;8(1):68. doi: 10.1038/s41523-022-00430-0.
PubMed 35610260Caparica R, Ma Y, De Angelis C, Richard F, Desmedt C, Awada A, Piccart M, Perez EA, Moreno-Aspitia A, Badve S, Thompson EA, de Azambuja E. Beta-2 Adrenergic Receptor Gene Expression in HER2-Positive Early-Stage Breast Cancer Patients: A Post-hoc Analysis of the NCCTG-N9831 (Alliance) Trial. Clin Breast Cancer. 2022 Jun;22(4):308-318. doi: 10.1016/j.clbc.2021.11.012. Epub 2021 Dec 2.
PubMed 34980541Chumsri S, Li Z, Serie DJ, Mashadi-Hossein A, Colon-Otero G, Song N, Pogue-Geile KL, Gavin PG, Paik S, Moreno-Aspitia A, Perez EA, Thompson EA. Incidence of Late Relapses in Patients With HER2-Positive Breast Cancer Receiving Adjuvant Trastuzumab: Combined Analysis of NCCTG N9831 (Alliance) and NRG Oncology/NSABP B-31. J Clin Oncol. 2019 Dec 10;37(35):3425-3435. doi: 10.1200/JCO.19.00443. Epub 2019 Oct 17.
PubMed 31622131Chumsri S, Serie DJ, Li Z, Pogue-Geile KL, Soyano-Muller AE, Mashadi-Hossein A, Warren S, Lou Y, Colon-Otero G, Knutson KL, Perez EA, Moreno-Aspitia A, Thompson EA. Effects of Age and Immune Landscape on Outcome in HER2-Positive Breast Cancer in the NCCTG N9831 (Alliance) and NSABP B-31 (NRG) Trials. Clin Cancer Res. 2019 Jul 15;25(14):4422-4430. doi: 10.1158/1078-0432.CCR-18-2206. Epub 2019 Feb 26.
PubMed 30808774Norton N, Fox N, McCarl CA, Tenner KS, Ballman K, Erskine CL, Necela BM, Northfelt D, Tan WW, Calfa C, Pegram M, Colon-Otero G, Perez EA, Clynes R, Knutson KL. Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer. Breast Cancer Res. 2018 Jun 14;20(1):52. doi: 10.1186/s13058-018-0989-8.
PubMed 29898752Perez EA, Ballman KV, Tenner KS, Thompson EA, Badve SS, Bailey H, Baehner FL. Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer. JAMA Oncol. 2016 Jan;2(1):56-64. doi: 10.1001/jamaoncol.2015.3239.
PubMed 26469139Perez EA, Baehner FL, Butler SM, Thompson EA, Dueck AC, Jamshidian F, Cherbavaz D, Yoshizawa C, Shak S, Kaufman PA, Davidson NE, Gralow J, Asmann YW, Ballman KV. The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831. Breast Cancer Res. 2015 Oct 1;17(1):133. doi: 10.1186/s13058-015-0643-7.
PubMed 26429296O'Sullivan CC, Bradbury I, Campbell C, Spielmann M, Perez EA, Joensuu H, Costantino JP, Delaloge S, Rastogi P, Zardavas D, Ballman KV, Holmes E, de Azambuja E, Piccart-Gebhart M, Zujewski JA, Gelber RD. Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors </= 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. J Clin Oncol. 2015 Aug 20;33(24):2600-8. doi: 10.1200/JCO.2015.60.8620. Epub 2015 Jun 22.
PubMed 26101239Perez EA, Thompson EA, Ballman KV, Anderson SK, Asmann YW, Kalari KR, Eckel-Passow JE, Dueck AC, Tenner KS, Jen J, Fan JB, Geiger XJ, McCullough AE, Chen B, Jenkins RB, Sledge GW, Winer EP, Gralow JR, Reinholz MM. Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial. J Clin Oncol. 2015 Mar 1;33(7):701-8. doi: 10.1200/JCO.2014.57.6298. Epub 2015 Jan 20.
PubMed 25605861Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. doi: 10.1200/JCO.2014.55.5730. Epub 2014 Oct 20.
PubMed 25332249Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. doi: 10.1200/JCO.2011.36.7045. Epub 2011 Oct 31.
PubMed 22042958Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. doi: 10.1056/NEJMoa052122.
PubMed 16236738